According to the Diagnostic and Statistical Manual for Mental Disorders, 5th Edition (DSM-5), opioid use disorder is characterized by signs and symptoms that reflect compulsive, prolonged self-administration of opioid substances that are used for no legitimate medical purpose or, if another medical condition is present that requires opioid treatment, they are used in doses greatly in excess of the amount needed for that medical condition. In a 2015 report from the National Survey on Drug Use and Health, 12.4 million Americans engaged in non-medical use of prescription pain relievers, including opioids. Approximately 2.06 million Americans met criteria for prescription pain reliever use disorder. The same report suggested that 5.1 million people aged 12 and older have used heroin at some point in their lives, with 828,000 using in the past year and 329,000 using in the past month. There were approximately 580,000 people who had a heroin use disorder in the past year. Perhaps most concerning, deaths from overdose of opioid analgesics (including opioids, methadone and other synthetic narcotics) showed a 5.2-fold increase from 5,528 to 28,647 deaths between 2001 and 2015. Similarly, heroin-related overdose fatalities showed a 5.4-fold increase during this same period, from 1,779 deaths in 2001 to 12,989 in 2015. An emerging concern contributing to recent increases in opioid overdose deaths were 9,580 deaths due to synthetic opioids (other than methadone) which increased 72% in one year (since 2014).
Opioid receptors are located in both the central nervous system (CNS) and the periphery. In the CNS, they are found in high concentrations in the limbic system and the spinal cord. The natural ligands for the opioid receptors are a group of neuropeptides known as endorphins. Opioid analgesics mimic the action of these natural ligands, but have a more prolonged action as they are not subject to rapid local metabolism. Three major opioid receptor subclasses have been identified: μ-, κ- and δ-. Buprenorphine is a partial agonist at the μ-opioid receptor, an antagonist at the κ- and δ-opioid receptors and an agonist at the nociceptin/orphanin FQ (N/OFQ) receptor. In contrast to a full agonist at the μ-opioid receptor, buprenorphine has less maximal euphoric effect, and a ceiling on its respiratory depressant effects. By binding to μ-opioid receptors in the brain, buprenorphine reduces craving for opioids and opiate withdrawal symptoms, minimizing the need of opioid-dependent patients to use illicit opiate drugs. For the maintenance treatment of opioid use disorder, SUBUTEX® tablets (buprenorphine; Indivior, Inc.), SUBOXONE® tablets (buprenorphine/naloxone; Indivior, Inc.), or SUBOXONE® film (buprenorphine/naloxone; Indivior, Inc.) may be given as a single daily dose.
The disclosure provides dosing regimens of sustained-release buprenorphine formulations that provide, among other benefits, optimal dosages, optimal treatment periods, therapeutic steady-state buprenorphine plasma concentrations, and therapeutic steady-state μ-opioid receptor occupancy in the brain for the treatment of opioid use disorder.